Marine biodiversity as a source of chemical diversity

Total global biodiversity is estimated at between 3 and 500 × 10⁶ species of prokaryote and eukaryote organisms spread across 70 or more phyla. The marine macrofauna alone are estimated between 0.5 and 30 × 10⁶ species and represents a broader range of taxonomic diversity than that found in the terrestrial environment, which has been the traditional source of natural products. With a typical eukaryote possessing 50,000 genes, the global marine macrofauna are the source of 2.5 × 10¹⁰ to 1.5 × 10¹² primary products and an associated extensive range of secondary products. However, only a few thousand novel compounds from marine organisms have been described. These compounds have proven unique in chemical and pharmacological terms but, as yet, no therapeutic agents have resulted. Given a broader drug discovery strategy, and facilitated by technological advances, it is predicted that the characterisation of marine chemical diversity will be accelerated. Strategies for drug discovery from the virtually untapped chemical diversity of marine organisms are discussed. © 1994 Wiley-Less, Inc.     

A Pharmacoeconomic Model to Evaluate Antibiotic Costs

Study Objectives . To characterize patient sociodemographics and health, describe vancomycin treatment parameters and clinician-rated outcomes, and determine costs associated with treatment including preparation and administration, adverse events, and toxicity. Design . A prospective study to develop a model for costs associated with antibiotic treatment (vancomycin). Setting . A community hospital. Patients . One hundred adults with active infections. Interventions . Mean duration of therapy was 10 days, and most patients received 2000 mg/day. Serum concentrations were monitored in two of three patients. Detailed cost analyses were completed on a subset of 26 patients selected at random from the overall sample. Measurements and Main Results . Sepsis and skin and skin structure infections were the most common indications for vancomycin therapy. Treatment was effective in 81 patients, failed in 9, and was not evaluable in 10. Thirty-eight percent of patients experienced adverse events attributable to the drug. Phlebitis was common, and red man syndrome, nephrotoxicity, and ototoxicity were infrequent. Conclusions . Total cost of vancomycin treatment for 100 patients was $30,251: $23,855 for preparation and administration, $1710 for monitoring serum concentrations, and $4686 for treating adverse reactions. Drug costs accounted for only 55% of the total cost. Vancomycin is safe and effective, but phlebitis is underreported and significantly affects cost.     

Disposition of Tablet and Capsule Formulations of Digoxin in the Elderly

Study Objective . To compare digoxin tablets and liquid-filled capsules with respect to excretion of the drug and its metabolites in urine and feces at steady state. Design . A randomized, crossover trial, each period lasting 3 weeks, with no washout period. Setting . A university hospital. Patients . Six patients, five of whom were elderly, with histories of gastrointestinal disorders, such as hypochlorhydria, intestinal bacterial overgrowth, and inflammatory bowel disease. Interventions . The patients received digoxin once/day in either tablet or capsule form for 3 weeks, and then were switched to the other formulation. Total urinary and fecal excretion from the last 3 days of each regimen were analyzed for the drug and metabolites. Measurements and Main Results . No statistically significant differences were found between tablets and capsules in recovery of digoxin or its metabolites in urine or feces (p=0.05). One subject had a 4-fold increase in urinary drug excretion and 50% decrease in fecal excretion after taking the capsules compared with tablets. Intersubject variability in extent and type of metabolite excretion was greater than intrasubject variability. Conclusions . Fecal analyses may be an accurate way to classify patients as formers of digoxin reduction products.     

INTERACTIONS BETWEEN THE CIRCULATORY EFFECTS OF CENTRAL HYPOVOLAEMIA AND ARTERIAL HYPOXIA IN CONSCIOUS RABBITS

1. Eight conscious rabbits were repeatedly subjected to progressive reduction in central blood volume by gradually inflating a thoracic inferior vena caval-cuff so cardiac index (CI) fell at a constant 8.5% of baseline/min. 2. Caval-cuff inflations were performed after 10 min exposure to 100, 21, 12–14 and 8–10% O₂, with and without the addition of 3–4% CO₂, in randomized order. 3. The haemodynamic response to progressive reduction in central blood volume was biphasic. In Phase I, systemic vascular conductance index (SVCI) fell linearly, supporting mean arterial pressure (MAP). When CI had fallen to a critical level, Phase II occurred in which SVCI rose abruptly, MAP plummeted and respiratory drive progressively increased. 4. During Phase I, there were independent linear relationships between Pao₂ (but not Pao₂) and the rates at which SVCI and MAP changed during the progressive fall of CI. The higher the level of Pao₂, the greater was the rate of fall of SVCI and the less the rate of fall of MAP. 5. There was an inverted U-shaped effect of Pao₂, on the level of CI at which Phase II occurred: (a) during hyperoxia (100% O₂), Phase II occurred later than during normoxia (21% O₂); and (b) across the normoxic and hypoxic gas mixtures (21–8% O₂, with and without added CO₂), there was an independent linear relationship between Pao₂ (but not Pao₂ or Pao₂×Pao₂) and the level of CI at which Phase II occurred. That is, the lower the level of Pao₂, the later was the onset of Phase II. This interaction is best explained by an increased level of central sympathetic vasoconstrictor drive during hypoxia.     

The bioavailability and nonlinear pharmacokinetics of MK-679 in humans

MK-679 (R(?)-3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)(3-(dimethylamino)-3-oxopropyl)thio)methyl)thio(propanoic acid) is a potent and specific LTD₄-receptor antagonist. The disposition of MK-679 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma concentration—time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two-compartment model with linear tissue distribution and Michaelis-Menten elimination from the central compartment, indicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-dependent when given together with its S(+)-isomer, L-668,018. Thus, the disposition of MK-679 in humans is dose-dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK-679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg ¹⁴C-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nearly quantitative.     

Grip and pinch strength among selected adult occupational groups

A survey of 402 normal subjects (203 men, 199 women) was conducted to assist in distinguishing potential differences in norms of hand strength. Norm data had previously been collected from mixed occupational groups, but in the present study it was hypothesised that people involved in heavy manual work on a daily basis might possess greater hand strength than others. The volunteers were adults working in industry and agriculture; they were subdivided into occupational categories. Measurements of grip, key and palmar pinch using the Jamar dynamometer and B and L pinch gauge were collected, using the protocol described by Mathiowetz. Volunteers also rated their individual hand strength job requirements subjectively. Mean values were established with regard to age, sex, dominance, occupational group and subjective rating. Significant differences were found with regard to age and sex but not to dominance; there was no evidence of differences between occupational groups or between subjective rating and individual scoring, i.e. volunteers who perceived their job as requiring a high degree of strength did not achieve higher test measurements than others. A high interrater reliability was demonstrated when comparing these follow-up measurements with the original data. It was concluded that, for clinical and rehabilitative purposes, therapists can interpret assessment of outcome most accurately by comparing patients' results with the existing norm data.     

Developmental cellular electrophysiologic effects of propafenone on the rabbit atrioventricular node.

Transmembrane recordings and surface electrograms were used to evaluate the influence of propafenone on the cellular electrophysiology of isolated neonatal and adult rabbit atrioventricular node (AVN) preparations. An automatic interval of 863 +/- 82 ms (mean +/- SEM, n = 14) in neonates was found to be significantly shorter than the 1510- +/- 205-ms (n = 12) automatic interval observed in adults. Propafenone in a concentration of 5 x 10(-6) M significantly increased the automatic interval of neonatal pacemakers but not that of the adult preparations. These changes in automaticity produced by propafenone were not dependent on the adrenergic receptor-blocking action of the drug. The pacemaker escape time after overdrive pacing was also shorter in the neonate than in the adult. Propafenone prolonged the escape time of the neonatal tissues but not those of the adult. AVN refractory period, A-H interval, and antegrade Wenckebach rate were comparably increased in a concentration-dependent manner in both age groups. The maximum diastolic potential was decreased by propafenone in the neonatal atrionodal tissue but not in other regions of the AVN and not in any region of the adult AVN. Action-potential duration was increased in all regions of the AVN in both age groups. Action-potential amplitude and maximum upstroke velocity were decreased by propafenone in both age groups. Unlike other excitable tissues of the heart, the action-potential duration of AVN nodal cells increased with decreasing pacing intervals as the pacing interval approached the Wenckebach interval.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preventing accidental injury to young children in the home using volunteers

Accidental injury in the home is a major cause of death andill-health among young children. Reducing home safety hazardsby the use of safety devices such as stair barriers and safetytaps has the potential to prevent home injuries. Little is knownabout levels of home safety hazards or how to encourage parentsto reduce hazards. The Safe Place Project examined parents'knowledge of home safety and the prevalence of safety hazardsin homes where there were young children. The study also evaluatedthe effectiveness of a low-cost strategy aimed at reducing homesafety hazards. The strategy used trained volunteers to providehome safety checks and tailored safety education in conjunctionwith increasing the availability of home safety devices. Onehundred and six families with young children participated inthe project. Some homes contained many hazards, with 43% ofthe sample having more than 10 home safety hazards. At follow-up,the intervention group showed a significant reduction in homehazards and a trend towards an increase in knowledge of homesafety.